Rasmussen encephalitis (RE) is a rare but severe chronic inflammatory brain disease of
unknown origin affecting one brain hemisphere. It is usually accompanied by intractable
epilepsy. In addition, it often leads to severe disability due to functional deficits caused
by atrophy of one brain hemisphere. Hemispherectomy is an effective means of surgical
treatment of the epilepsy. It renders the patient, however, hemiplegic, hemianopic and (if
the language dominant hemisphere is affected) aphasic. To slow down or even stop the
progressive inflammatory damage to the affected brain hemisphere, immunotherapies may be
beneficial. According to a literature survey, tacrolimus (twice daily intake of capsules) and
intravenous immunoglobulins (monthly infusions) are the most promising compounds for this. In
our study, these two types of treatment are randomly assigned to patients with disease onset
within the last year and not too far advanced disability or hemispheric brain injury. The
patients are followed to assess prospectively the functional and brain MRI course of the
disease.

Clinical Details

Official title: Efficacy of Tacrolimus and i.v.-Immunoglobulins in Rasmussen Encephalitis With Start of Treatment in the Acute Disease Stage. Prospective, Randomised, Open Parallel Group Study

Study design: Treatment, Randomized, Open Label, Parallel Assignment

Primary outcome: Time to exit, criteria: Deterioration of motor function of the affected side by 15 % (>11 yrs of age: 8%) measured by the "Motricity Index" (scale 0-100) or deterioration of the "Hemispheric ratio" assessed by regular MRI scans by 15% (>11 yrs: 8%).

Detailed description:
1. Trial design/2. Trial interventions Patients are screened in epileptological,
neuropediatric, and neurological centers all over Germany. The study design was approved on a
meeting in Bonn on April 20, 2002 by several external participants and by the ethical
committee of the University of Bonn. Patients with the suspected diagnosis of RE are
transferred to the Department of Epileptology of the University of Bonn. If the diagnosis "RE
in the acute stage" is confirmed and the patient or (in children) the parents give informed
consent, the patients are randomized to one of the two active treatment arms.

The study was started on 1. 10. 2002. The first patient was included on 20. 11. 2002.

3. Inclusion/exclusion criteria See appropriate section

4. Duration Recruitment started on 1. 10. 2002 and will go on until the proposed number of
study participants has been included. A patient remains in the study until he or she reaches
one of the predefined exit parameters (see below, #4. 5). Every patient will be followed under
study conditions for at least 12 months (to obtain true long term results).

5. Outcome measures See appropriate section.

6. Methods against bias The patients will be randomized to one of the treatment arms. To
avoid unbalanced group sizes and unequal numbers of adolescents and adults, there are two
randomization lists, one for patients < 11 years, one for older patients (stratification).
Blinding is not possible because the administration of the two drugs is different and would
have necessitated the additional use of placebo capsules in the IVIG group and placebo
infusions in the tacrolimus group. Because the production and administration of an adequate
"IVIG-placebo" is highly impracticable, no blinded treatment application was planned. The
physicians assessing the "Motricity Index" and the "Hemispheric ratio" are unaware of the
kind of treatment used.

7. Power calculations It is assumed that 1-2 RE patients are diagnosed at a large epilepsy
center per year. The cooperation of the study center with the other specialized centers in
Germany is good. Therefore, it is expected that the majority of RE cases are transferred to
or department. We estimated that 16 suitable patients can be included within the proposed
inclusion period. The disease is too rare to perform power calculations (which are mainly
used to limit recruitment figures). RE is an orphan disease, so even if the number of
participants will not suffice to detect small to moderated differences between the two
treatments, the results will provide invaluable information on the conservative treatment of
the condition, e. g. in comparison to historical untreated controls.

8. Number of participants It is intended to include at least 16 patients during the above
named period (otherwise, the recruitment period will be prolonged). We will perform an
intention to treat analysis and an analysis of the patients treated per protocol.

9. Trial sites Potential study participants are referred to our department (Dept. of
Epileptology, University of Bonn) from all over Germany. The study procedures, especially the
clinical and neuroradiological follow-up studies including assessment of safety parameters
are performed in Bonn (visits every two months within the first year, in the second year
every four months, thereafter every six months). In the intervals between the visits in Bonn,
the referring centers participate in monitoring of the patients and administration of IVIG.
There is continuous contact between the study center Bonn and the external study co-workers.

10. Analyses Primary outcome parameter (time to exit): The two groups will be compared by the
log rank test (Kaplan-Meyer-survival curves). Non-parametric tests will be applied for the
secondary outcome parameters.

11. Ethical considerations Tacrolimus and IVIG can have side effects. The known tacrolimus
side effects are more severe and more frequent than those of IVIG. It must be noted, however,
that the known tacrolimus side effects were assessed in organ transplant patients who had
severe medical diseases and were usually treated with more than one immunosuppressant. In
patients with autoimmune disorders treated with tacrolimus-monotherapy, the side effects were
considerably lower. RE itself is a disease with a deleterious natural course so that the
possible risks of an immunotherapy are clearly outweighed. It must be assumed that most RE
patients worldwide are treated with any kind of immunotherapy in the early disease stage due
to the favorable case reports in the literature. Therefore, a placebo control group appears
ethically unacceptable. This is why we chose to compare the two most promising substances.
The ethics committee of the University of Bonn has approved the study design.